A new technique has been developed which permits simultaneous measurement of blood: brain barrier permeability and cerebral blood flow (CBF), in the rat. This is accomplished by concurrent measurement of CBF and of the extraction fraction of water (EW). CBF is measured by entrapment of radioisotope-labeled microspheres. Ew is determined from the proportional uptake of 3H-water to 14C-butanol. Once Ew and CBF are known, the effective permeability of the blood: brain barrier (PS) is determined as: PS equals 1n (1-Ew) CBF. Preliminary work has established the practicality of this technique and has yielded normative data for future work. The new technique provides an inexpensive means of studying the blood: brain barrier in almost any research environment. Previously, studies of permeability and flow have required expensive support facilities and the use of large animals, making such research impractical for most investigators. This study will utilize the new technique to further understanding of the effect of a commonly-prescribed tricyclic antidepressant, amitriptyline, on cerebral vascular dynamics. Previous studies have demonstrated that amitriptyline, at concentrations approximating therapeutic levels in man, elevates Ew in the rat. It is unclear, however, whether this effect is caused by increased blood: brain barrier permeability or reduced cerebral blood flow. Thus, it is not known whether this drug increases or decreases the rate at which simple molecules may be delivered to or cleared from the brain. The proposed project will resolve this question. The enhanced understanding of the effects of amitriptyline on the blood: brain barrier and on cerebral blood flow which will be gained may lead to improvement in the rational use of antidepressant chemotherapy and to a better understanding of the pathophysiology underlying affective disorders.